Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections. Darunavir has HIV protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. Among them darunavir, chemically (1S,2R,3′R,3′aS,6′aR)-[3′-hexahydrofuro[2,3-b]furanyl-[3-(4-aminobenzenesulfonyl)isobutylamino]-1-benzyl-2-hydroxypropyl]carbamate. Darunavir is represented by the following structure:

Darunavir and its pharmaceutical acceptable salts such as hydrochloride were described in EP 715618.
Processes for the preparations of darunavir were disclosed in EP 715618, WO 99/67417, U.S. Pat. No. 6,248,775, and in Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998, “Potent HIV protease inhibitors incorporating high-affinity P2-igands and (R)-(hydroxyethylamino)sulfonamide isostere”, all of which are incorporated herein by reference.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
Darunavir or its hydrochloride salt can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. Patent Application No. 2005/0250845 described amorphous form, form A (ethanolate), form B (hydrate), form C (methanolate), form D (acetonate), form E (dichloromethanate), form F (ethylacetate solvate), form G (1-ethoxy-2-propanolate), form H (anisolate), form I (tetrahydrofuranate), form J (isopropanolate) and form K (mesylate) of darunavir.
Darunavir C5-C8 alcohol solvate and process for its preparation was disclosed in co-pending Application No. PCT/IN2009/000724. According to the application also disclosed a process for the preparation of darunavir amorphous form which comprises a solution of darunavir C5-C8 alcohol solvate in dichloromethane, removing the solvent from the solution to obtain a residue, slurrying the residue with cyclohexane and isolating.
We have discovered novel crystalline hydrochloride salt of darunavir and also discovered novel process for the preparation of darunavir amorphous form.
Thus, one object of the present invention is to provide novel crystalline hydrochloride salt of darunavir, process for its preparation and to pharmaceutical compositions comprising it.
The salt of the present invention may also serve as intermediates for preparation of darunavir amorphous form and other polymorphs of darunavir.
Another object of the present invention is to provide a novel process for preparation of darunavir amorphous form and pharmaceutical compositions comprising it.